Compounds and Compositions as Protein Kinase Inhibitors

ABSTRACT

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders than involve abnormal activation of the Abl, Bcr-abl, Bmx, c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR, JNK1α 1, JNK2α 2, Lck, MKK4, MKK6, p70S6K, PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and Trkβ kinases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/582,467 (filed 23 Jun. 2004) and U.S.Provisional Patent Application No. 60/588,563 (filed 15 Jul. 2004). Thefull disclosures of these applications are incorporated herein byreference in their entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated withabnormal or deregulated kinase activity, particularly diseases ordisorders that involve abnormal activation of the Abl, Bcr-abl, Bmx,c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR, JNK1α1, JNK2α2, Lck, MKK4,MKK6, p70S6K, PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and TrkB kinases.

2. Background

The protein kinases represent a large family of proteins, which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function. A partial, non-limiting,list of these kinases include: receptor tyrosine kinases such asplatelet-derived growth factor receptor kinase (PDGF-R), the nervegrowth factor receptor, trkB, and the fibroblast growth factor receptor.FGFR3; non-receptor tyrosine kinases such Ab1 and the fusion kinaseBCR-Abl, Lck, Csk, Fes, Bmx and c-src; and serine/threonine kinases suchas c-RAF, sgk, MAP kinases (e.g., MKK4, MKK6, etc) and SAPK2α andSAPK2β. Aberrant kinase activity has been, observed in many diseasestates including benign and malignant proliferative disorders as well asdiseases resulting from inappropriate activation of the immune andnervous systems.

The novel compounds of this Invention inhibit the activity of one ormore protein kinases and are, therefore, expected to be useful in thetreatment of kinase-associated diseases.

SUMMARY OF FEE INVENTION

In one aspects the present invention provides compounds of Formula I:

in which:

Y is selected from C, P(O), and S(O);

R₁ is selected from hydrogen. C₁₋₆alky, C₆₋₁₀aryl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alky andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl;

R₂ is selected from hydrogen and C₁₋₆alky or

R₁ and R₂ together with the nitrogen atom to which R₁ and R₂ areattached form C₃₋₁₀ heterocycloalkyl or C₅₋₁₀heteroaryl;

wherein any alkyl of R₁ can be optionally substituted by one to threeradicals independently chosen from halo, C₁₋₆alkoxy and —XNR₇R₈; whereinX is a bond or C₁₋₆alkylene; and R₇ and R₈ are independently chosenfront hydrogen and C₁₋₆alkyl;

wherein any aryl, heterosryl, cycloalkyl or heterocycloalkyl of R₁, orthe combination of R₅ and R₂, is optionally substituted by one to threeradicals chosen from halo, hydroxy, C₁₋₆alkyl, —XOXNR₇R₉ and —XR₁₀;wherein X is a bond or C₁₋₆alkylene; R₇ and R₈ are independently chosenfrom hydrogen and C₁₋₆alkyl; and R₁₀ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl C₃₋₁₀cycloalkyl and C₃₋₁₀ heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₀ is optionallysubstituted by 1 to 3 radicals chosen from halo, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy and —XNR₇R₉radicals; wherein X is a bond or C₁₋₆alkylene; and R₇ and R₈ areindependently chosen from hydrogen and C₁₋₆alkyl;

R₃ and R₄ are independently chosen from hydrogen and C₁₋₆alkyl;

R₅ is selected from C₁₋₆alkyl C₂₋₆-alkenyl C₁₋₆alkoxy,halo-substituted-C₁₋₄alkyl and halo-substituted-C₁₋₄-alkoxy;

R₆ is selected from C₆₋₁₀-aryl C₅₋₁₀-heteroaryl, C₃₋₁₀-cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein any aryl heteroaryl cycloalkyl orheterocycloalkyl of R₆ is optionally substituted by one to threeradicals independently chosen from halo, amino, nitro, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl halo-substituted C₁₋₆alkoxy,—XNR₇R7, —XNR₇XNR₇R7, —XNR₇C(O)R₇, —XC(O)OR₇, —XNR₇S(O)₂R₇, —XNR₇S(O)R₇,—XNR₇SR₇ and —XR₁₁; wherein X and R₇ are as defined above and R₁₁ isselected from the group consisting of C₅₋₁₀heteroaryl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any heteroaryl orheterocycloalkyl of R₁₁ is optionally substituted with a radicalselected from the group consisting of C₁₋₆alkyl,halo-substituted-C₁₋₆alkyl and —C(O)OR₇; and the N-oxide derivatives,prodrug derivatives, protected derivatives, individual isomers andmixture of isomers thereof; and the pharmaceutically acceptable saltsand solvates (e.g. hydrates) of such compounds.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof; or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which inhibition of kinase activity,particularly Abl, Bcr-abl, Bmx, c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR,JNK1α1, JNK2α2, Lck, MKK4, MKK6, p70S6K, PDGFRα, Rsk1, SAFK2α, SAPK2β,Syk and/or TrkB activity, can prevent, inhibit or ameliorate thepathology and/or symptomology of the diseases, which method comprisesadministering to the animal a therapeutically effective amount of acompound of Formula I or a N-oxide derivative, individual isomers andmixture of isomers thereof, or a pharmaceutically acceptable saltthereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which kinase activity, particularly Ab1, Bcr-abl, Bmx,c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR, JNK1α1, JNK2α2, Lck, MKK4,MKK6, p70Syk, PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and/or TrkB activity,contributes to the pathology and/or symptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₄alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl may be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group.

“Heteroaryl” is as defined for aryl above where one or more of the ringmembers is a heteroatom. For example heteroaryl includes pyridyl,indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, etc.

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Heterocycloalkyl” means cycloalkyl as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the Invention includes morpholino, pyrrolidinyl,pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone,1,4-dJoxa-8-aza-spiro[4.5]dec-8-yl, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but may alsobe bromo or iodo.

“Kinase Panel” is a list of kinases comprising Abl (human), Abl (T315I),JAK2, JAK3, ALK, JNK1α1, ALK4, KDR, Aurora-A, Lck, Blk, MAFK1, Bmx,MAPKAP-K2, BRK, MEK1, CaMKII(rat), Met, CDK1/cyclinB, p70S6K, CHK2,PAK2, CK1, PDGFRα, CK2, PDK1, c-kit, Pim-2, c-RAF, PKA(h), CSK, PKBα,cSrc, PKCα, DYRK2, Plk3, EGFR, ROCK-I, Fes, Ron, FGFR3, Ros, Flt3,SAPK2α, Fms, SGK, Fyn, SIK, GSK3β, Syk, IGF-IR, Tie-2, IKKβ, TrKB, IR,WNK3, IRAK4, ZAP-70, ITK, AMPK(rat), LIMK1, Rsk2, Ax1, LKB1, SAFK2β,BrSK2, Lyn (h), SAPK3, BTK, MAPKAP-K3, SAPK4, CaMKIV, MARK1, Snk,CDK2/cyclinA, MJNK, SRPK1, CDKB/cycliaE, MKK4(m), TAKI, CDR5/p25,MKK6(h), TBK1, CDK6/cyclinD3, MLCK, TrkA, CDK7/cyclinH/MAT1, MRCKJβ,TSSK1, CHK1, MSK1, Yes, CK1d, MST2, ZIPK, c-Kit (D816V), MuSK, DAPK2,NEK2, DRR₂, NEK6, DMPK, PAK4, DRAK1, PAR-1β, EphA1, PDGFRβ, EphA2,Pim-1, EphA5, PKBβ, EphB2, PKCβI, EphaB4, PKCδ, FGPR₁, PKCη, FGFR2,PKCθ, FGFR4, PKD2, Fgr, PKG1β, Flt1, PRK2, Hck, PYK2, HIPK2, Ret, IKKα,RIPK2, IRR, ROCK-II(human), JNK2α2, Rse, JNK3, Rsk1(h), PI3 Kγ, PI3 Kδand PI3-Kβ. Compounds of the invention are screened against the kinasepanel (wild type and/or mutation thereof) and inhibit the activity of atleast one of said panel members.

“Mutant forms of BCR-Abl” means single or multiple amino acid changesfrom the wild-type sequence. Mutations in BCR-ABL act by disruptingcritical contact points between protein and inhibitor (for example,Gleevec, and the like), more often, by inducing a transition from theinactive to the active state, i.e. to a conformation to which BCR-ABLand Gleevec is unable to bind. From analyses of clinical samples, therepertoire of mutations found in association with the resistantphenotype has been increasing slowly but inexorably over time. Mutationsseem to cluster in four main regions. One group of mutations (G250E,Q252R, Y253F/H, E255K/V) includes amino acids that to thephosphate-binding loop for ATP (also known as the P-loop). A secondgroup (V289A, F311L, T315I, F317L) can be found in the Gleevec bindingsite and interacts directly with the inhibitor via hydrogen bonds or Vander Waals' interactions. The third group of mutations (M351T, E355G)clusters in close proximity to the catalytic domain. The fourth group ofmutations (H396R/P) is located in the activation loop, whoseconformation is the molecular switch controlling kinaseactivation/inactivation. BCR-ABL point mutations associated with Gleevecresistance detected in CML and ALL patients include: M224V, L248V,G250E, G250R, Q252R, Q252H, Y253H, Y253F, E255K, E255V, D276G, T277A,V289A, F311L, T315I, T315N, F317L, M343T, M315T, E355G, F359V, P359A,V379I, F382L, L387M, L387F, H396P, H396, A397P, S417Y, E459K, and F486S(Amino acid positions, indicated by the single letter code, are thosefor the GenBaak sequence, accession number AAB60394, and correspond toABL type 1a; Martinelli et ah, Haematologica/The Hematology Journal,2005, April; 90-4). Unless otherwise stated for this invention, Bcr-Ab1refers to wild-type and mutant forms of the enzyme.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The fusion protein BCR-Abl is a result of a reciprocal translocationthat fuses fee Ab1 proto-oncogene with the Bcr gene. BCR-Abl is thencapable of transforming B-cells through the increase of mitogenicactivity. This increase results in a reduction of sensitivity toapoptosis, as well as altering the adhesion and homing of CML progenitorcells. The present invention provides compounds, compositions andmethods for the treatment of kinase related disease, particularly Abl,Bcr-abl, Bmx, c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR, JNK1α1, JNK2α2,Lck, MKK4, MKK6, p70S6K, PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and TrkBkinase related diseases. For example, leukemia and other proliferationdisorders related to BCR-Abl can be treated through the Inhibition ofwild type and mutant forms of Bcr-Ab1.

In one embodiment, with reference to compounds of Formula I, Y is C; R₁is selected from hydrogen, C₀₋₄alkyl, C₆₋₁₀alkyl-C₀₋₄alkyl,C₅₋₁₀heteroaryl-C₀₋₄alkyl, C₃₋₁₀cycloalkyl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; R₂ is selected from hydrogen andC₁₋₆alkyl; or R₁ and R₂ together with the nitrogen atom to which R₁ andR₂ are attached form C₃₋₁₀heterocycloalkyl; wherein any alkyl of R₁ canbe optionally substituted by one to three radicals independently chosenfrom C₁₋₆alkoxy and—XNR₇R₈; wherein X is a bond or C₁₋₆alkylene; and R₇and R₈ are independently chosen from hydrogen and C₁₋₆alkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁, or thecombination of R₁ and R₂, is optionally substituted by one to threeradicals chosen from hydroxy, C₁₋₆alkyl, —XOXNR₇R₈ and —XR₁₀; wherein Xis a bond or C₁₋₆alkylene; R₇ and R₈ are independently chosen fromhydrogen and C₁₋₆alkyl; and R₁₀ is selected from C₆₋₁₀aryl andC₃₋₁₀heterocycloalkyl; wherein any aryl or heterocycloalkyl of R₁₀ isoptionally substituted by 1 to 3 radicals chosen from, halo, C₁₋₆alkyland XNR₇R₈ radicals; wherein X is a bond or C₁₋₆alkylene; and R₇ and R₈are independently chosen from hydrogen and C₁₋₆alkyl.

In another embodiment, R3, R₄ and R₅ are independently chosen fromhydrogen and C₁₋₆alkyl; and R₆ is C₆₋₁₀aryl optionally substituted by 1to 3 radicals independently chosen from halo-substituted-C₁₋₆alkyl and—XR₁₁; wherein X is as defined above and R₁₁ is selected from the groupconsisting of C₅₋₁₀heteroaryl-C₀₋₄alkyl andC₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any heteroaryl orheterocycloalkyl of R₁₁ is optionally substituted with C₁₋₅alkyl.

In another embodiment, R₁ is selected from hydrogen, methyl, ethyl,6-methyl-pyridin-3-yl, 3-(2-oxo-pyrrolidin-1-yl)-propyl, pyridin-3-yl,3-methyl-isothiazol-5-yl, methoxy-ethyl, isopropyl, methyl-phenyl,morpholino-ethyl, cyclopropyl, diethyl-amino-ethyl, pyrrolidinyl-ethyl,pyridinyl-methyl, 4-hydroxy-cyclohexyl, benzo[1,3]dioxol-5-yl,4-morpholino-phenyl, 3-dimethylamino-phenyl,4-(2-morpholin-4-yl-ethyl-phenyl and diethyl-amino-ethoxy; R₂ isselected from hydrogen, methyl and ethyl; or R₁ and R₂ together with thenitrogen atom to which R₁ and R₂ are attached form 4-ethyl-piperazinylor 4-(3-aminophenyl)-piperazin-1-yl.

In a further embodiment, R₃ is methyl, R₄ is methyl, R₅ is hydrogen andR₆ is phenyl optionally substituted with 1 to 2 radicals selected fromtrifluoromethyl, morpholino, methyl-imidazolyl,methyl-piperazinyl-methyl, ethyl-piperazinyl and methyl-piperazinyl.

Preferred compounds are selected from:N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-morpholin-4-yl-5-trifluoromethyl-benzamide;N-[4-methyl-3-(8-methyl-2-(6-methyl-pyridin-3-ylamino)-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-[4-methyl-3-[8-methyl-2-[4-morpholin-4-yl)phenylamino]-7-oxo-7,8-dihydropteridin-6-yl]-phenyl]-3-trifluoromethyl-benzamide;N-[3-(2-Dimethylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-3-{2-[(2-Methoxy-ethyl)-methyl-amino]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl}-4-methyl-phenyl)-3-trifluormethyl-benzamide;N-[3-(2-Isopropylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-7-oxo-2-p-tolylamino-7,8-dihydro-pteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-2-(2-morpholin-4-yl-ethylamino-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(4-Ethyl-piperazin-1-yl)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Cyclopropylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(2-Diethylamino-ethylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-7-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-7-oxo-2-[(pyridin-4-ylmethyl)-amino]-7,8-dihydro-pteridin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;N-[3-(2-Diethylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(4-Hydroxy-cyclohexylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{-3-[2(Benzo[1,3]dioxol-5-ylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{2-[4-(3-Amino-phenyl)-piperazin-1-yl]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-{3-[2-(3-Dimethylamino-phenylamino)-8-Methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]-7-oxo-7,8-dihydro-pteridin-6-yl}-phenyl)-3-trifluromethyl-benzamide;N-(3-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;3-(4-Methyl-imidazol-1-yl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-4-morpholin-4-yl-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[2-methylamino-8-(2-morpholin-4-yl-ethyl)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-7-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-7,8-dihydro-pteridin-6-yl}phenyl)-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-7-oxo-2-(pyridin-3-ylamino-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{4-methyl-3-[8-methyl-2-(3-methyl-isothiazol-5-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;3-(4-Ethyl-piperazin-1-yl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl-phenyl]-5-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl-phenyl]-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide;4-(4-Ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(2,6-Dimethyl-pyridin-3-ylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{4-methyl-3-[8-methyl-2-(2-methyl-pyridin-3-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(4,6-Dimethyl-pyridin-3-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-4-morpholin-4-yl-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-morpholin-4-yl-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-ethyl-piperazin-1-yl-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl-4-methyl-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide;andN-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide.

Further preferred compounds of the invention are detailed in theExamples and Table I, infra.

Pharmacology and Utility

Compounds of the invention modulate the activity of kinases and, assuch, are useful for treating diseases or disorders in which kinases,contribute to the pathology and/or symptomology of the disease. Examplesof kinases that are inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include, but are not limited to, Abl, BCR-Abl (wild-type andmutant forms), Bmx, c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR, JNK1α1,JNK2α23 Lck, MKK4, MKK6, p70S6K, PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk andTrkB.

Abelson tyrosine kinase (i.e. Abl, c-Abl) is involved in the regulationof the cell cycle, in the cellular response to genotoxic stress, and inthe transmission of information about the cellular environment throughintegrin signaling. Overall, it appears that the Ab1 protein serves acomplex role as a cellular module that integrates signals from variousextracellular and intracellular sources and that influences decisions inregard to cell cycle and apoptosis, Abelson tyrosine kinase includessub-types derivatives such as the chimeric fusion (oncoprotein) BCR-Ablwith deregulated tyrosine kinase activity or the v-Abl. BCR-Abl iscritical in the pathogenesis of 95% of chronic myelogenous leukemia(CML) and 10% of acute lymphocytic leukemia. STI-571 (Gleevec) is aninhibitor of the oncogenic BCR-Abl tyrosine kinase and is used for thetreatment of chronic myeloid leukemia (CML). However, some patients inthe blast crisis stage of CML are resistant to STI-571 due to mutationsin the BCR-Abl kinase. Over 22 mutations have been reported to date withthe most common being G250E, E255V, T3151, F317L and M351T.

Compounds of the present invention inhibit abl kinase, especially v-ablkinase. The compounds of the present invention also inhibit wild-typeBCR-Abl kinase and mutations of BCR-Abl kinase and are thus suitable forthe treatment of Bcr-abl-positive cancer and tumor diseases, such asleukemias (especially chronic myeloid leukemia and acute lymphoblasticleukemia, where especially apoptotic mechanisms of action are found),and also shows effects on the subgroup of leukemic stem cells as well aspotential for the purification of these cells in vitro after removal ofsaid cells (for example, bone marrow removal) and reimplantation of thecells once they have been cleared of cancer cells (for example,reimplantation of purified bone marrow cells).

PDGF (Platelet-derived Growth Factor) is a very commonly occurringgrowth factor, which plays an important role both in normal growth andalso in pathological cell proliferation, such as is seen incarcinogenesis and in diseases of the smooth-muscle cells of bloodvessels, for example in atherosclerosis and thrombosis. Compounds of theinvention can inhibit PDGF receptor (PDGFR) activity and are, therefore,suitable for the treatment of tumor diseases, such as gliomas, sarcomas,prostate tumors, and tumors of the colon, breast, and ovary.

Compounds of the present invention, can be used not only as atumor-inhibiting substance, for example in small cell lung cancer, butalso as an agent to treat non-malignant proliferative disorders, such asatherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis, aswell as for the protection of stem cells, for example to combat thehemotoxic effect of chemotherapeutic agents, such as 5-fluoruracil, andin asthma. Compounds of the invention can especially be used for thetreatment of diseases, which respond to an inhibition of the PDGFreceptor kinase.

Compounds of the present invention show useful effects in the treatmentof disorders arising as a result of transplantation, for example,allogenic transplantation, especially tissue rejection, such asespecially obliterative bronchiolitis (OB), i.e. a chronic rejection ofallogenic lung transplants. In contrast to patients without OB, thosewith OB often show an elevated PDGF concentration in bronchoalveolarlavage fluids.

Compounds of the present invention are also effective in diseasesassociated with vascular smooth-muscle cell migration and proliferation(where PDGF and PDGF-R often also play a role), such as restenosis andatherosclerosis. These effects and the consequences thereof for theproliferation or migration of vascular smooth-muscle cells in vitro andin vivo can be demonstrated by administration of the compounds of thepresent invention, and also by investigating its effect on thethickening of the vascular intima following mechanical injury in vivo.

The compounds of the present invention also inhibit cellular processesinvolving stem-cell factor (SCF, also known as the c-kit ligand or steelfactor), such as inhibiting SCF receptor (kit) autophosphorylation andSCF-stimulated activation of MAPK kinase (mitogen-activated proteinkinase). MO7e cells are a human promegakaryocytic leukemia cell line,which depends on SCF for proliferation. Compounds of the invention caninhibit the autophosphorylation of SCF receptors.

The trk family of neurotrophin receptor (trkA, trkB, trkC) promotes thesurvival, growth and differentiation of the neuronal and non-neuronaltissues. The TrkB protein is expressed in neuroendocrine-type cells inthe small intestine and colon, in the alpha cells of the pancreas, inthe monocytes and macrophages of the lymph nodes and of the spleen, andin the granular layers of the epidermis (Shibayama and Koizumi, 1996).Expression of the TrkB protein has been associated with an unfavorableprogression of Wilms tumors and of neuroblastomas. TkrB is, moreover,expressed in cancerous prostate cells but not in normal cells. Thesignaling pathway downstream of the trk receptors involves the cascadeof MAPK activation through the She, activated Ras, ERK-1 and ERK-2genes, and the PLC-gammal transduction pathway (Sugimoto et al. 2001).

The kinase, c-Src transmits oncogenic signals of many receptors. Forexample, over-expression of EGFR or HER2/neu in tumors leads to theconstitutive activation of c-src, which is characteristic for themalignant cell but absent from the normal cell. On the other hand, micedeficient in the expression of c-src exhibit an osteopetrotic phenotype,indicating a key participation of c-src in osteoclast function and apossible involvement in related disorders.

The Tec family kinase, Bmx, a non-receptor protein-tyrosine kinase,controls the proliferation of mammary epithelial cancer cells.

Fibroblast growth factor receptor 3 was shown to exert a negativeregulatory effect on bone growth and an inhibition of chondrocyteproliferation. Thanatophoric dysplasia is caused by different mutationsin fibroblast growth factor receptor 3, and one mutation, TII FGFR3, hasa constitutive tyrosine kinase activity which activates thetranscription factor Stat1, leading to expression of a cell-cycleinhibitor, growth arrest and abnormal bone development (Su et al.,Nature, 1997, 386, 28S-292). FGFR₃ is also often expressed in multiplemyeloma-type cancers.

The activity of serum and glucocorticoid-regulated kinase (SGK), iscorrelated to perturbed ion-channel activities, in particular, those ofsodium and/or potassium channels and compounds of the invention can beuseful for treating hypertension.

Lin et al (1997) J. Clin. Invest. 100, 8; 2072-2078 and P. Lin (1998)PNAS 95, 8829-8834, have shown an inhibition of tumor growth andvascularization and also a decrease in lung metastases during adenoviralinfections or during injections of the extracellular domain of Tie-2(Tek) in breast tumor and melanoma xenograft models. Tie2 inhibitors canbe used in situations where neovascularization takes placeinappropriately (i.e. in diabetic retinopathy, chronic inflammation,psoriasis, Kaposi's sarcoma, chronic neovascularization due to maculardegeneration, rheumatoid arthritis, infantile haemangioma and cancers).

Lck plays a role in T-cell signaling. Mice that lack the Lck gene have apoor ability to develop thymocytes. The function of Lck as a positiveactivator of T-cell signaling suggests that Lck inhibitors may be usefulfor treating autoimmune disease such as rheumatoid arthritis.

JNKs, along with other MAPKs, have been implicated in having a role inmediating cellular response to cancer, thrombin-induced plateletaggregation, immunodeficiency disorders, autoimmune diseases, celldeath, allergies, osteoporosis and heart disease. The therapeutictargets related to activation of the JNK pathway include chronicmyelogenous leukemia (CML), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer and neurodegenerative diseases. As aresult of the importance of JNK activation associated with liver diseaseor episodes of hepatic ischemia, compounds of the invention may also beuseful to treat various hepatic disorders. A role for JNK incardiovascular disease such as myocardial infarction or congestive heartfailure has also been reported as it has been shown JNK mediateshypertrophic responses to various forms of cardiac stress. It has beendemonstrated that the JNK cascade also plays a role in T-cellactivation, including activation of the IL-2 promoter. Thus, inhibitorsof JNK may have therapeutic value in altering pathologic immuneresponses. A role for JNK activation in various cancers has also beenestablished, suggesting the potential use of JNK inhibitors in cancer.For example, constitutively activated JNK is associated with HTLV-1mediated tumorigenesis [Oncogene 13:135-42 (1996)]. JNK may play a rolein Kaposi's sarcoma (KS). Other proliferative effects of other cytokinesimplicated in KS proliferation, such as vascular endothelial growthfacto (VEGF), IL-6 and TNFα, may also be mediated by JNK, in addition,regulation of the c-jun gene in p210 BCR-ABL transformed cellscorresponds with activity of JNK, suggesting a role for JNK inhibitorsin the treatment for chronic myelogenous leukemia (CML) [Blood92:2450-60 (1998)].

Certain abnormal proliferative conditions are believed to be associatedwith raf expression and are, therefore, believed to be responsive toinhibition of raf expression. Abnormally high levels of expression ofthe raf protein are also implicated in transformation and abnormal cellproliferation. These abnormal proliferative conditions are also believedto be responsive to inhibition ofraf expression. For example, expressionof the e-raf protein is believed to play a role in abnormal cellproliferation since it has been reported that 60% of all lung carcinomacell lines express unusually high levels of c-raf mRNA and protein.Further examples of abnormal proliferative conditions arehyper-proliferative disorders such as cancers, tumors, hyperplasia,pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and smoothmuscle cell proliferation in the blood vessels, such as stenosis orrestenosis following angioplasty. The cellular signaling pathway ofwhich raf is a part has also been implicated in inflammatory disorderscharacterized by T-cell proliferation (T-cell activation and growth),such as tissue graft rejection, endotoxin shock, and glomerularnephritis, for example.

The stress activated protein kinases (SAPKs) are a family of proteinkinases that represent the penultimate step in signal transductionpathways that result in activation of the c-jun transcription factor andexpression of genes regulated by c-jun. In particular, c-jun is involvedin the transcription of genes that encode proteins involved in therepair of DNA that is damaged due to genotoxic insults. Therefore,agents that inhibit SAPK activity in a cell prevent DNA repair andsensitize the cell to agents that induce DNA damage or inhibit DNAsynthesis and induce apoptosis of a cell or that inhibit cellproliferation.

Mitogen-activated protein kinases (MAPKs) are members of conservedsignal transduction pathways that activate transcription factors,translation factors and other target molecules in response to a varietyof extracellular signals. MAPKs are activated by phosphorylation at adual phosphorylation motif having the sequence Thr-X-Tyr bymitogen-activated protein kinase kinases (MKKs). In higher eukaryotes,the physiological role of MAPK signaling has been correlated withcellular events such as proliferation, oncogenesis, development anddifferentiation. Accordingly, the ability to regulate signaltransduction via these pathways (particularly via MKK4 and MKK6) couldlead to the development of treatments and preventive therapies for humandiseases associated with MAPK signaling, such as inflammatory diseases,autoimmune diseases and cancer.

Syk is a tyrosine kinase that plays a critical role in mast celldegranulation and eosinophil activation. Accordingly, Syk kinase isimplicated in various allergic disorders, in particular asthma. It hasbeen shown that Syk binds to the phosphorylated gamma chain of the FcsR1receptor via N-terminal SH2 domains and is essential for downstreamsignaling.

Inhibition of eosinophil apoptosis has been proposed as a key mechanismfor the development of blood and tissue eosinophilia in asthma. IL-5 andGM-CSF are upregulated in asthma and are proposed to cause blood andtissue eosinophilia by inhibition of eosinophil apoptosis. Inhibition ofeosinophil apoptosis has been proposed as a key mechanism for thedevelopment of blood and tissue eosinophilia in asthma. It has beenreported that Syk kinase is required for the prevention of eosinophilapoptosis by cytokines (using antisense) [Yousefi, et al., J. Exp. Med.1996, 183, 1407].

The family of human ribosomal S6 protein kinases consists of at least 8members (RSK1, RSK2, RSK3, RSK4, MSK1, MSK2, p70S6K and p70S6 Kb).Ribosomai protein S6 protein kinases play important pleotropicfunctions, among them is a key role in die regulation of mRNAtranslation during protein biosynthesis (Eur. J. Biochem 2000 November,267(21): 6321-30, Exp Cell Res. Nov. 25, 1999; 253 (1): 100-9, Mai CellEndocrinol. May 25, 1999; 151(1-2):65-77). The phosphorylation of the S6ribosomal protein by p70S6 has also been implicated in the regulation ofcell motility (Immunol Cell Biol. 2000 August; 78(4):447-51) and cellgrowth (Prog. Nucleic Acid Res. Mol. Biol. 2000; 65:101-27), and hence,may be important in tumor metastasis, the immune response and tissuerepair as well as other disease conditions.

The SAPK's (also called “jun N-terminal kinases” or “JNK's”) are afamily of protein kinases that represent the penultimate step in signaltransduction pathways that result in activation of the c-juntranscription factor and expression of genes regulated by c-jun. Inparticular, c-jun is involved in the transcription of genes that encodeproteins involved in the repair of DNA that is damaged due to genotoxicinsults. Agents that inhibit SAPK activity in a cell prevent DNA repairand sensitize the cell to those cancer therapeutic modalities that actby inducing DNA damage.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

Administration and Pharmaceutical Compositions

to general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca, 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g. magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcelluose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations may also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such maycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other immunomodulatory or antiinflammatory substances, forexample when used in combination with cyclosporin, rapamycin, orascomycin, or immunosuppressant analogues thereof, for examplecyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparablecompounds, corticosteroids, cyclophosphamide, azathioprine,methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid,mycophenolate mofetil, 15-deoxyspergualin, immunosuppressant antibodies,especially monoclonal antibodies for leukocyte receptors, for exampleMHC, CD2, cD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, orother immunomodulatory compounds, such as CTLA41g. Where fee compoundsof the invention are administered in conjunction with other therapies,dosages of the co-administered compounds will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The terra “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions,Conventional protecting groups can be used in accordance with standardpractice, for example, see T.W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the followingReaction Scheme I:

in which Y, R₁, R₂, R₃, R₄, R₅ and R₆ are as defined for Formula I inthe Summary of the Invention. A compound of Formula I can be prepared byreacting a compound of formula 2 with a compound of formula 3 in thepresence of a suitable coupling reagent (e.g., HATU, or the like) and asuitable solvent (e.g., THF, BMP, or the like). The reaction proceeds ina temperature range of about room temperature to about 80° C. and canlake up to about 20 hours to complete.

Compounds of Formula I can be prepared by proceeding as in the followingReaction Scheme 2:

in which Y, R₁, R₂, R₃, R₄, R₅ and R₆ are as defined for Formula I inthe Summary of the Invention. A compound of Formula I can be prepared byreacting a compound of formula 4 with a compound of formula 5 by threemethods. For the heteroaryl amine or aryl amine, the reaction proceedsin the presence of a suitable catalyst (e.g., Pd (II) salt, or the like)and a suitable solvent (e.g., 1,4-dioxane, or the like), in atemperature range of about 80 to about 150° C. and can take up to about20 hours to complete. The reaction conditions for alkyl aminedisplacement involves heating a compound of formula 4 with 5-10equivalents of amine hi a suitable solvent (e.g. DMSO, DMF, or thelike). For condensations of formula 4 with aryl amine, these are bestcarried out in the presence of acid (e.g., TsOH, HOAc, HCL or the like)in a suitable solvent (e.g., DMSO, DMF, alcohol or the like).

Detailed examples of the synthesis of a compound of Formula I can befound in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamoylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T.W. Greene, “Protecting Groupsin Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 198.1.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) those of reaction schemes I and II; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing examples that illustrate the preparation of compounds ofFormula I according to the invention.

Example 1N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-morpholin-4-yl-5-trifluoromethyl-benzamide

2-chloro-4-(methyl-amino)-5-nitropyrimidine

A solution of 2,4-dichloro-5-nitropyrimidine (7.26 g, 37.4 mmol) in THP(100 ml) is cooled to −78° C. A solution of methyl amine (8 M inmethanol, 9.35 mL, 74.8 mmol) is added dropwise. The mixture is allowedto warm to room temperature, and concentrated. The residue ispartitioned between ethyl acetate and water. The layer is separated andthe aqueous layer is extracted with ethyl acetate. The combined organicextracts are washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford the title product (7.0 g). (Note: the productcontains 5% regio-isomer, 4-chloro-2-(methylamino)-5-nitropyrimidine).The residue is used in the next step without further purification.

2,4-(dimethylamino)-5-nitropyrimidine

To a solution of 2-chloro-4-(methylamino)-5-nitropyrimidine (0.644 g,3.42 mmol, synthesized from the above procedure) in ethanol (20 mL) isadded 2M methyl amine in THF (10 mL). After stirring for 3 hours at roomtemperature, the solvent is removed under vacuum. The solid is washedwith, water, dried to afford the title compound (620 mg, 99%).

5-amino-2,4-(dimethylamino)-pyrimidine

After hydrogenation of 2,4-(dimethylamino)-5-nitropyrimidine overpalladium on charcoal (Pd/C), 1 atm H₂, the title compound is made inHCl salt form and used for the next reaction without any furtherpurification.

N-acetyl-3-bromo-4-methylaniline

To a solution of 3-bromo-4-methylaniline (1.27 g, 6.82 mmol) in DCM (20mL) at (0° C. is added acetic anhydride (0.676 mL, 7.16 mmol) dropwise.After 30 minutes, the mixture is partitioned between DCM and saturatedsodium carbonate solution. The layer is separated and the aqueous layeris extracted with DCM. The combined organic extracts are washed withbrine, dried over Na₂SC₄, filtered and concentrated to afford the titlecompound (1.55 g, 99%). The residue is used in the next step withoutfurther purification.

Ethyl 2-(5-acetylamino-2-methylphenyl)-2-oxoacetate

To a solution of N-acetyl-3-bromo-4-methylaniline (1.43 g, 627 mmol) inTOT (50 mL) at −78° C. is added 2M BuLi in pentane (7.83 mL, 15.66 mmol)dropwise. After a further 1 h, diethyl oxalate (4.26 mL, 31.3 mmol) isadded. After stirring for 4 hours at −78°, the reaction mixture isquenched with saturated NH₄Cl solution. The mixture is partitionedbetween ethyl acetate and water. The layer is separated and the aqueouslayer is extracted with ethyl acetate. The combined organic extracts arewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue is purified by column chromatography (silica gel, eluting withethyl acetate; hexanes from 1/1 to 2/1) to afford fee title compound(0.82 g, 52%).

6-(5-Amino-2-methylphenyl)-8-methyl-2-methylamino-8H-petridin-7-one

A mixture of ethyl 2-(5-acetylamino-2-methylphenyl-2-oxoacetate (223 mg,0.85 mol), 5-amino-2,4-(dimethylamino)-pyrimidine (211 mg, HCl salt) inethanol (20 mL) is heated at 100° C. in a sealed tube. After heating for1 day, 5N HCl in isopropanol (5 mL) is added and the mixture is heatedunder reflux for 6 h before the solvent is removed under vacuum. Then,the mixture is basified with saturated sodium carbonate solution. Thesolid is filtered and dried to afford the title compound as agreen-yellow powder 120 mg. The filtrated liquid is extracted withEtOAc. Further purification by column chromatography (silica gel,eluting with ethyl acetate:hexanes 1/1 to ethyl acetate) affordedanother form of title compound 80 mg.

To a solution of6-(5-amino-2-methylphenyl)-8-methyl-2-methylamino-8H-petridin-7-one(19.8 mg, 0.067 mmol), 3-(4-morpholin-4-yl)-5-Trifluoromethylbenzoicacid (22 mg, 0.08 mmol), and DIEA (46 μL, 0.26 mmol) in DMF (3 mL) isadded HATU (30 mg, 0.08 m mol). After stirring for 1 hour at roomtemperature, the solvent is removed under vacuum. The residue isdissolved in DMSO (1 mL). The resulting solution is subjected topurification by reverse-phase LC-MS to yield the title compound; ¹H NMR400 MHz (DMSO-d₆) δ10.37 (s, 1H), 8.76 (s, 0.3H), 8.68 (s, 0.7H), 8.04(s, 0.7H), 7.94 (s, 03H), 7.77 (dd, 1H, J=8.3, 3.0 Hz), 7.75-7.73 (m,2H), 7.67 (s, 1H), 7.39 (s, 1H), 7.27 (d, 1H, J=8.8 Hz), 3.77 (t 4H,J=4.4 Hz), 3.65 (s, 3H), 3.30 (t, 4H, J=4.4 Hz), 2.94 (s, 3H), 2.19 (s,3H); MS m/z 554.2 (M+ 1).

Example 2N-[4-methyl-3-(8-methyl-3-(8-methyl-3-(6-methyl-pyridin-3-ylamino)7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide

5-amino-2-chloro-4-(methylamino)-pyrimidine

A mixture of 2-chloro-4-(methylamino)-5-nitropyrimidine (3.76 g, 20mmol, synthesized from the above procedure), tin(II) chloride dihydrate(18.0 g, 80 mmol) in ethanol (200 mL) is heated at 80° C. After heatingfor 2 hours, the reaction mixture is cooled to room temperature andconcentrated. Ethyl acetate and celite is added to the residue and themixture is basified with saturated sodium carbonate solution to a pH of9-10. The mixture is filtered through a pad of celite and washed withethyl acetate. The combined organic extracts are washed with brine,dried over Na₂SO₄, filtered and concentrated. Further purification bycolumn chromatography (silica gel, eluting with ethyl acetate) affordsthe title compound (1.72 g, 54%).

N-[4-Methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide

A mixture of ethyl2-[5-(3-trifluoromethylbenzoylamino-2-methylphenyl)-2-oxoacetate (840mg, 2.21 mmol), 5-amino-2-chloro-4-(methylamino)-pyrimidine (702 mg,4.42 mmol), acetic acid (1 mL) in isopropanol (15 mL) is heated at 110°C. in a sealed tube. After heating for 32 h, the solvent is removedunder vacuum. Then, the residue is partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The layer is separated and theaqueous layer is extracted with ethyl acetate. The combined organicextracts are washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue is purified by column chromatography (silicagel, eluting with EtOAc/Hexanes gradient) to afford the title compound(550 mg, 52%).

A Smith vial (2-5 ml) is charged withN-[4-methyl-3-(2-chloro-8-methyl-7-OXO-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide(31 mg, 0.065 mmol), 5-amino-2-methylpyridine (14 mg, 0.13 mmol),Pd(OAc)₂ (1.5 mg, 0.0065 mmol), Xantphos (5.7 mg, 0.01 mmol), Cs₂CO₃ (43mg, 0.13 mmol) and 1,4-dioxane (2 mL). After purged with Argon, the vialis sealed and irradiated at 150° C. for 15 minutes in a SmithSynthesizer. The solid is filtered off and washed with acetone. Thecombined filtrate is concentrated and purified by column chromatography(silica gel, elating with ethyl acetate) to yield the title compound; 1HNMR 400 MHz (DMSO-d₆) δ10.92 (s, 1H), 10.58 (s, 1H), 9.25 (s, 1H), 9.02(s, 1H), 8.58 (d, 1H), 8.33 (s, 1H), 8.30 (d, 1H), 7.98 (d, 1H), 7.90(d, 1H), 7.80 (m, 3H), 7.33 (d, 1H), 3.67 (s, 3H), 2.69 (s, 3H), 2.24(s, 3H); MS m/z 546.10 (M+1).

Example 3N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide

A Smith vial (2-5 mL) is charged withN-[4-methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-pheny]-3-trifluoromethyl-benzamide(15 mg, 0.032 mmol), 2M methylamine solution in THF (160 μL, 0.32 mmol),and DMSO (0.5 mL). After purging with Argon, the vial is sealed andirradiated at 100° C. for 45 minutes in a Smith Synthesizer. Theresulting solution is subjected to purification by reverse-phase LC-MSto yield the title compound; ¹HNMR 400 MHz (DMSO-d₆) δ10.51 (s, 1H),8.68 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (bs, 1H), 7.96(d, J=7.2 Hz, 1H), 7.80-7.76 (m, 3H), 7.27 (d, J=8.2 Hz, 1H), 3.56 (s,3H), 2.94 (s, 3H), 2.19 (s, 3H); MS m/z 469.3 (M+1).

Example 4N-[4-methyl-3-[8-methyl-2-[4-morpholin-4-yl)phenylamino]-7-oxo-7,8-dihydropteridin-6-yl]-phenyl]-3-trifluoromethyl-benzamide

A Smith vial (2-5 mL) is charged withN-[4-methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-phenyl-]-3-trifluormethyl-benzamide(12 mg, 0.025 mmol), 4-morpholin-4-yl-phenylamine (14 mg, 0.078 mmol),p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol), and DMSO (0.5mL). After purging with Argon, the vial is sealed and irradiated at 100°C. for 1.5 hours in Smith Synthesizer. The resulting solution issubjected to purification by reverse-phase LC-MS to yield the titlecompound; ¹H NMR. 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 10.16 (bs, 1H),8.83 (s, 1H), 8.32 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.96 (d, J=8.0 Hz,1H), 7.84-7.81 (m, 1H), 7.81-7.75 (m, 2H), 7.75-7.69 (m, 2H), 7.29 (d,J=8.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.62 (s,3H), 3.12 (t, J=4.8 Hz, 4H), 2.22 (s, 3H); MS m/z 616.4 (M+1).

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1, are obtained. TABLE 1 Physical Data ¹H NMR 400MHz Compound (DMSO-d₆) and/or Number Structure MS (m/z) 5

¹H NMR 400 MHz (DMSO-d₆) δ 10.51 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H),8.27 (d, J=7.2 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.82-7.66 (m, 3H), 7.27(d, J=8.0 Hz, 1H), 3.56 (s, 3H), 3.27 (s, 6H), 2.20 (s, 3H); MS m/z483.4 (M + 1). 6

¹H NMR 400 MHz (DMSO-d₆) δ 10.51 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H),8.27 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.82-7.66 (m, 3H), 7.28(d, J=8.8 Hz, 1H), 3.90 (bs, 3H), 3.50-3.62 (m, 4H), 3.29 (s, 3H), 3.27(s, 3H), 2.19 (s, 3H); MS m/z 527.4 (M + 1). 7

¹H NMR 400 MHz (DMSO-d₆) δ 10.51 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H),8.27 (d, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H),7.82-7.66 (m, 3H), 7.27 (d, J=8.8 Hz, 1H), 4.18 (m, 1H), 3.57 (s, 3H),3.27 (s, 6H), 2.19 (s, 3H), 1.25-1.19 (m, 6H); MS m/z 497.4 (M + 1). 8

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 10.22 (s, 1H), 8.86 (s, 1H),8.31 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.83-7.81(m, 1H), 7.81-7.78 (m, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz,1H), 7.18 (d, J=8.0 Hz, 2H), 3.63 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H);MS m/z 545.4 (M + 1). 9

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H),8.26 (d, J=7.2 Hz, 1H), 8.18 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.84 (m,1H), 7.79 (d, J=7.6 Hz, 1H), 7.77-7.71 (m, 1H), 7.29 (d, J=8.0 Hz, 1H),4.06-3.94 (m, 2H), 383-3.74 (m, 4H), 3.68 (m, 2H), 3.55 (s, 3H),3.46-3.34 (m, 2H), 3.22-3.10 (bs, 2H), 2.19 (s, 3H); MS m/z 568.4 (M +1). 10

¹H NMR 400 MHz (DMSO-d₆) δ 10.54 (s, 1H), 9.81 (bs, 1H), 8.87 (s, 1H),8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.85 (d,J=2.8 Hz, 1H), 7.82-7.72 (m, 2H), 7.29 (d, J=8.8 Hz, 1H), 4.91 (d,J=13.6 Hz, 2H), 3.80-3.60 (m, 3H), 3.44 (t, J=13.2 Hz, 4H), 3.22-3.18(m, 2H), 3.18-3.04 (m, 2H), 2.20 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); # MSm/z 552.4 (M + 1). 11

¹H NMR 400 MHz (DMSO-d₆) δ 10.52 (s, 1H), 8.31 (s, 1H), 8.27 (d, J=7.6Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.82-7.74 (m, 4H), 7.28 (d, J=8.8 Hz,1H), 3.56 (bs, 3H), 2.90 (s, 1H), 2.19 (s, 3H), 0.77 (m, 2H), 0.58 (m,2H); MS m/z 495.3 (M +1). 12

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 9.40-9.22 (m, 1H), 8.77 (s,1H), 8.31 (s, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.84(s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.78-7.71 (m, 1H), 7.29 (d, J=8.4 Hz,1H), 3.62 (m, 4H), 3.55 (bs, 3H), 3.38-3.16 (m, 6H), 2.20 (s, 3H), 1.22(t, J=7.2 Hz, 6H); MS m/z 554.4 (M + 1). 13

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 9.72-9.55 (m, 1H), 8.77 (s,1H), 8.31 (s, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H),7.87-7.81 (m, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.78-7.71 (m, 1H), 7.29 (d,J=8.4 Hz, 1H), 3.64-3.58 (m, 4H), 3.58-3.54 (m, 2H), 3.48-3.36 (bs, 3H),3.14-3.02 (m, 2H), 2.20 (s, 3H), 2.08-1.98 (bs, 2H), 1.94-1.81 (bs,# 2H); MS m/z 552.4 (M +1). 14

¹H NMR 400 MHz (DMSO-d₆) δ 10.52 (s, 1H), 8.84-8.76 (m, 3H), 8.30 (s,1H), 8.26 (d, J=7.6 Hz, 1H), 7.99-7.92 (m, 3H), 7.91-7.84 (m, 1H),7.81-7.77 (m, 2H), 7.77-7.71 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.58 (s,2H), 3.39 (s, 3H), 3.14-3.02 (m, 2H), 2.20 (s, 3H), 2.17 (s, 3H); MS m/z546.4 (M + 1). 15

¹H NMR 400 MHz (DMSO-d₆) δ 10.52 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H),8.27 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.81-7.75 (m, 3H), 7.28(d, J=8.8 Hz, 1H), 3.78-3.66 (bs, 4H), 3.57 (s, 3H), 2.19 (s, 3H),1.30-1.12 (m, 6H); MS m/z 511.4 (M + 1). 16

¹H NMR 400 MHz (DMSO-d₆) δ 10.51 (s, 1H), 8.67 (s, 1H), 8.31 (s, 1H),8.27 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.81-7.75 (m, 3H), 7.27(d, J=9.2 Hz, 1H), 3.57 (s, 3H), 3.52 (m, 1H), 2.19 (s, 3H), 2.07 (m,1H), 2.02-1.83 (m, 4H), 1.44-1.20 (m, 4H); MS m/z 553.3 (M +1). 17

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 10.21 (bs, 1H), 8.85 (s, 1H),8.31 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.84-7.81(m, 1H), 7.81-7.75 (m, 2H), 7.54 (bs, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.22(d, J=7.6 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 6.02 (s, 2H), 3.62 (s, 3H),2.22 (s, 3H); MS m/z 575.3 (M + 1). 18

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 8.82 (s, 1H), 8.31 (s, 1H),8.27 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.82 (m, 1H), 7.82-7.74(m, 2H), 7.32-7.24 (m, 2H), 6.91 (d, J=7.4 Hz, 1H), 6.78 (s, 1H), 6.64(d, J=7.4 Hz, 1H), 4.08 (m, 4H), 3.60 (s, 3H), 3.32 (m, 4H), 2.20 (s,3H); MS m/z 615.4 (M + 1). 19

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 10.18 (s, 1H), 8.87 (s, 1H),8.32 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85-7.82(m, 1H), 7.81-7.75 (m, 2H), 7.47 (bs, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.20(m, 2H), 656 (s, 1H), 3.66 (s, 3H), 2.96 (s, 6H), 2.22 (s, 3H); MS m/z574.4 (M + 1). 20

¹H NMR 400 MHz (DMSO-d₆) δ 10.53 (s, 1H), 10.33 (s, 1H), 8.89 (s, 1H),8.31 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.86 (m,1H), 7.85-7.80 (m, 2H), 7.80-7.74 (m, 2H), 7.33-7.27 (m, 3H), 4.02 (d,J=7.6 Hz, 2H), 3.68 (d, J=12.8 Hz, 2H), 3.64 (s, 3H), 3.52 (d, J=11.6Hz, 2H), 3.44-3.36 (m, 2H), 3.20-3.04 (m, 2H), 3.02-2.94 (m, 2H), # 2.22(s, 3H); MS m/z 644.4 (M + 1). 21

¹H NMR 400 MHz (DMSO-d₆) δ 10.54 (s, 1H), 10.23 (bs, 1H), 8.86 (s, 1H),8.31 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.85 (m,1H), 7.82-7.73 (m, 4H), 7.30 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H),4.34-4.28 (m, 2H), 3.62 (s, 3H), 3.56-3.50 (m, 2H), 3.31-3.18 (m, 4H),2.22 (m, 3H), 1.24 (t, J=7.2 Hz, 6H),; MS m/z 646.4 (M + 1). 22

¹H NMR 400 MHz (DMSO-d₆) δ 10.67 (s, 1H), 9.66 (s, 1H), 8.76 (s, 0.3H),8.68 (s, 0.7H), 8.61 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H),8.04 (br, 0.7H), 7.94 (br, 0.3H), 7.80 (dd, J=8.0, 2.0 Hz, 1H,), 7.76(d, J=2.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.63 (s, 3H), 2.94 (m, 3H),2.36 (s, 3H), 2.21 (s, 3H); MS m/z 549.20 (M + 1). 23

¹H NMR 400 MHz (DMSO-d₆) δ 10.41 (s, 1H), 8.76 (s, 0.3H), 8.68 (s,0.7H), 8.26-8.23 (m, 2H), 8.04 (br, 0.7H), 7.94 (br, 0.3H), 7.77-7.75(m, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 3.73 (t, J=4.8Hz, 4H), 3.60 (s, 3H), 2.95 (m, 7H), 2.19 (s, 3H); MS m/z 554.20 (M +1). 24

¹H NMR 400 MHz (DMSO-d₆) δ 10.50 (s, 1H), 9.68 (br, 1H), 8.76 (s, 0.3H),8.68 (s, 0.7H), 8.31 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.04 (br, 0.7H),7.94 (br, 0.3H), 7.91 (d, J=8.4 Hz, 1H,), 7.77 (m, 2H), 7.28 (d, J=8.8Hz, 1H), 3.79 (s, 2H), 3.60 (s, 3H), 3.40 (d, J=11.6 Hz, 2H), 3.07 (m,2H), 2.94-2.91 (m, 5H), 2.81 (s, 3H), 2.42 (t, J=11.6 Hz, 2H), # 2.20(s, 3H); MS m/z 581.20 (M + 1). 25

¹H NMR 400 MHz (DMSO-d₆) δ 10.50 (s, 1H), 9.96 (br, 1H), 8.83 (s, 0.3H),8.74 (s, 0.7H), 8.30 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 8.16 (br, 0.7H),7.94 (br, 0.3H), 7.90 (d, J=7.6 Hz, 1H,), 7.83 (s, 1H), 7.79 (t, J=7.6Hz, 1H), 7.68 (dd, J=8.4, 2.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 4.66 (m,2H), 4.01-3.51 (m, 8H), 3.20 (m, 2H), 2.95 (d, J=5.2 Hz, 3H), # 2.23 (s,3H); MS m/z 568.20 (M + 1). 26

¹H NMR 400 MHz (DMSO-d₆) δ 11.00 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H),8.28 (d, 1H), 7.97 (d, 1H), 7.80 (m, 3H), 7.49 (s, 2H,), 7.28 (d, 1H),3.54 (s, 3H), 2.20 (s, 3H); MS m/z 455.05 (M + 1). 27

¹H NMR 400 MHz (DMSO-d₆) δ 11.0 (s, 1H), 8.75 (s, 0.3H), 8.70 (s, 0.7H),8.30 (s, 1H), 8.28 (d, 1H), 8.08 (br, 0.7H), 7.97 (br, 0.3H), 7.96 (d,1H), 7.78 (m, 3H), 7.28 (d, 1H), 3.60 (s, 3H), 3.48 (m, 4H), 3.07 (m,2H), 3.28 (m, 2H), 3.22 (m, 5H), 1.95 (m, 2H), 1.80 (m, 2H); MS m/z580.10 (M + 1). 28

¹H NMR 400 MHz (DMSO-d₆) δ 11.0 (s, 1H), 10.56 (s, 1H), 9.36 (s, 1H),9.02 (s, 1H), 8.68 (d, 1H), 8.52 (d, 1H), 8.31 (s, 1H), 8.29 (d, 1H),7.98 (d, 1H), 7.90 (m, 2H), 7.80 (m, 2H), 7.32 (d, 1H), 3.60 (s, 3H),2.22 (s, 3H); MS m/z 532.10 (M + 1). 29

¹H NMR 400 MHz (DMSO-d₆) δ 10.52 (s, 1H), 9.00 (s, 1H), 8.32 (s, 1H),8.28 (d, 1H), 7.98 (d, 1H), 7.88 (s, 1H), 7.80 (m, 2H), 7.30 (d, 1H),6.82 (s, 1H), 3.80 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H); MS m/z 552.10(M + 1). 30

¹H NMR 400 MHz (DMSO-d₆) δ 10.52 (s, 1H), 10.1 (s, 1H), 8.87 (s, 1H),8.31 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.96 (d, 1 J=8.4 Hz, H), 7.83-7.77(m, 3H), 7.30 (d, J=8.0 Hz, 1H), 6.17 (s, 1H), 3.66 (s, 3H), 3.56 (s,3H), 2.22 (s, 3H), 2.16 (s, 3H); MS m/z 549.10 (M + 1). 31

MS m/z 581.25 (M +1). 32

MS m/z 567.24 (M +1). 33

MS m/z 595.27 (M +1). 34

MS m/z 560.19 (M +1). 35

MS m/z 564.18 (M +1). 36

MS m/z 560.19 (M +1). 37

MS m/z 540.19 (M +1). 38

MS m/z 535.17 (M +1). 39

MS m/z 540.19 (M +1). 40

MS m/z 567.24 (M +1). 41

MS m/z 553.22 (M +1). 42

MS m/z 567.24 (M +1). 43

MS m/z 581.25 (M +1).

Compounds of the present invention are assayed to measure their capacityto selectively inhibit cell proliferation of 321) cells expressingBCR-Abl (32D-p210) compared with parental 32D cells. Compoundsselectively inhibiting the proliferation of these BCR-Abl transformedcells are tested for anti-proliferative activity on Ba/F3 cellsexpressing either wild type or the mutant forms of Bcr-abl. In addition,compounds are assayed to measure their capacity to inhibit FGFR₃ (in anenzyme and cellular assay), FLT3, PDGFRβ, trkB, c-SRC, BMX, SGK, Tie2,Lck, JNK2α2, MKK4, c-RAF, MKK6, SAPK2α and SAPK2β kinases.

Inhibition of Cellular BCR-Abl Dependent Proliferation (High ThroughputMethod)

The murine cell line used is the 32D hemopoietic progenitor cell linetransformed with BCR-Abl cDNA (32D-p210). These cells axe maintained inRPMI/10% fetal calf serum (RPMI/FCS) supplemented with penicillin 50μg/mL, streptomycin 50 μg/mL and L-glutamine 200 mM. Untransformed 32Dcells are similarly maintained with the addition of 15% of WEHIconditioned medium as a source of IL3.

50 μl of a 32D or 32-Dp210 cells suspension are plated in Greiner 384well microplates (black) at a density of 5000 cells par well, 50 nl oftest compound (1 mM in DMSO stock solution) is added to each well(STI571 is included as a positive control). The cells are incubated for72 hours at 37° C., 5% CO₂. 10 μl of a 60% Alamar Blue solution (Tekdiagnostics) is added to each well and the cells are incubated for anadditional 24 hours. The fluorescence intensity (Excitation at 530 nm,Emission at 580 nm) is quantified using the Acquest™ system (MolecularDevices).

Inhibition of Cellular BCR-Abl Dependent Proliferation

32D-p210 cells are plated into 96 well TC plates at a density of 15,000cells per well. 50 μL of two fold serial dilutions of the test compound(C_(max) is 40 μM) are added to each well (STI571 is included as apositive control). After incubating the cells for 48 hours at 37° C., 5%CO₂, 15 μl, of MTT (Promega) is added to each well and the cells areincubated for an additional 5 hours. The optical density at 570 nm isquantified spectrophotometrically and IC₅₀ values, the concentration ofcompound required for 50% inhibition, determined from a dose responsecurve.

Effect on Cell Cycle Distribution

32D and 32D-p210 cells are plated into 6 well TC plates at 2.5×10⁶ cellsper well in 5 ml of medium and test compound at 1 or 10 μM is added(STI571 is included as a control). The cells are then incubated for 24or 48 hours at 37° C., 5% CO₂. 2 ml of cell suspension is washed withPBS, fixed in 70% EtOH for 1 hour and treated with PBS/EDTA/RNase A for30 minutes. Propidium iodide (Cf=10 μg/ml) is added and the fluorescenceintensity is qualified by flow cytometry on the FACScalibur™ system (BDBiosciences), Test compounds of the present invention demonstrate anapoptotic effect on the 32-Dp210 cells but do not induce apoptosis inthe 32D parental cells.

Effect on Cellular BCR-Abl Autophosphorylation

BCR-Abl autophosphorylation is quantified with capture Elisa using ac-abl specific capture antibody and an antiphosphotyrosine antibody.32-Dp210 cells are plated in 96 well TC plates at 2×10⁵ cells per wellin 50 μL of medium. 50 μL of two fold serial dilutions of test compounds(C_(max) is 10 μM) are added to each well (STI571 is included as apositive control). The cells are incubated for 90 minutes at 37° C., 5%CO₂. The cells are then treated for 1 hour on ice with 150 μL of lysisbuffer (50 mM Tris-HCL pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1%NP-40) containing protease and phosphatase inhibitors. 50 μL of celllysate is added to 0.96 well optiplates previously coated with anti-ablspecific antibody and blocked. The plates are incubated for 4 hours at4° C., After washing with TBS-Tween 20 buffer, 50 μL ofalkaline-phosphatase conjugated anti-phosphotyrosine antibody is addedand the plate is further incubated overnight at 4° C. After washing withTBS-Tween 20 buffer, 90 μL of a luminescent substrate are added and theluminescence is quantified using the Acquest™ system (MolecularDevices). Test compounds of the invention that inhibit the proliferationof the BCR-Abl expressing cells, inhibit the cellular BCR-Ablautophosphorylation in a dose-dependent manner.

Effect on Proliferation of Cells Expressing Mutant Forms of Bcr-Abl

Compounds of the invention are tested for their antiproliferative effecton Ba/F3 cells expressing either wild type or the mutant forms ofBCR-Abl (G250E, E255V, T315I, F317L, M351T) that confers resistance ordiminished sensitivity to STI571. The antiproliferative effect of thesecompounds on the mutant-BCR-Abl expressing cells and on the nontransformed cells were tested at 10, 3.3, 1.1 and 0.37 μM as describedabove (in media lacking IL3). The IC₅₀ values of the compounds lackingtoxicity on the untransformed cells were determined from the doseresponse curves obtained as describe above.

FGFR₃ (Enzymatic Assay)

Kinase activity assay with purified FGFR₃ (Upstate) is carried out in afinal volume of 10 μL containing 0.25 μg/mL of enzyme in kinase buffer(30 in M Tris-HCl pH7.5, 15 mM MgCl₂, 4.5 mM MnCl₂, 15 μM Na₃VO₄ and 50μg/mL BSA), and substrates (5 μg/mL biotin-poly-EY(Glu, Tyr) (CIS-US,Inc.) and 3 μM ATP). Two solutions are made: the first solution of 5 μlcontains the FGFR₃ enzyme in kinase buffer was first dispensed into384-format ProxiPlate® (Perkin-Elmer) followed by adding 50 nL ofcompounds dissolved in DMSO, then 5 μl of second solution contains thesubstrate (poly-EY) and ATP in kinase buffer was added to each wells.The reactions are incubated at room temperature for one hour, stopped byadding 10 μL of HTRF detection mixture, which contains 30 mM Tris-HClpH7.5, 0.5 M KF, 50 mM ETDA 0.2 mg/mL BSA, 15 μg/mL streptavidin-XL665(CIS-US, Inc.) and 150 ng/mL cryptate conjugated anti-phosphotyrosineantibody (CIS-US, inc.). After one hour of room temperature incubationto allow for streptavidin-biotin interaction, time resolved florescentsignals are read on Analyst GT (Molecular Devices Corp.), IC₅₀ valuesare calculated by linear regression analysis of the percentageinhibition of each compound at 12 concentrations (1:3 dilution from 50μM to 0.28 nM). In this assay, compounds of the invention have an IC₅₀in the range of 10 M to 2 μM,

FGFR₃ (Cellular Assay)

Compounds of the invention are tested for their ability to inhibittransformed Ba/F3-TBL-FGFR₃ cells proliferation, which is depended onFGFR₃ cellular kinase activity. Ba/F3-TEL-FGFR₃ are cultured up to800,000 cells/mL in suspension, with RPMI 1640 supplemented with 10%fetal bovine scrum as tire culture medium. Cells are dispensed into384-well format plate at 5000 cell/well in 50 μL culture medium.Compounds of the invention are dissolved and diluted in dimethylsufoxide(DMSO). Twelve points 1:3 serial dilutions are made into DMSO to createconcentrations gradient ranging typically from 10 mM to 0.05 μM, Cellsare added with 50 nL of diluted compounds and incubated for 48 hours incell culture incubator, AlamarBlue® (TREK Diagnostic Systems), which canbe used to monitor the reducing environment created by proliferatingcells, are added to cells at final concentration of 10%. Afteradditional four hours of incubation in a 37° C. cell culture incubator,fluorescence signals from reduced AlamarBlue® (Excitation at 530 nm,Emission at 580 nm) are quantified on Analyst GT (Molecular DevicesCorp.), IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition of each compound at 12 concentrations.

FLT3 and PDGFRB (Cellular Assay)

The effects of compounds of the invention on the cellular activity ofFLT3 and PDGFRβ are conducted using identical methods as described abovefor FGFR₃ cellular activity, except that instead of usingBa/F3TEL-FGFR3, Ba/P3-FLT3-ITD and Ba/F3-Tel-PDGFR are used,respectively.

Upstate KinaseProfiler™—Radio-Enzymatic Filter Binding Assay

Compounds of the invention are assessed for their ability to inhibitindividual members of the kinase panel. The compounds are tested induplicates at a final concentration of 10 μM following this genericprotocol, Note that the kinase buffer composition and the substratesvary for the different kinases included in the “Upstate KinaseProfiler™”panel. Kinase buffer (2.5 μL, 10x—containing MnCl₂ when required),active kinase (0.001-0.01 Units; 2.5 μL), specific or Poly(Glu-4-Tyr)peptide (5-500 μM or 0.01 mg/ml) in kinase buffer and kinase buffer (50μM; 5 μL) are mixed in an eppendorf on ice. A Mg/ATP mix (10 μL; 67.5(or 33.75) mM MgCl₂, 450 (or 225) μM ATP and 1 μCi/μl [γ-³²P]-ATP (3000Ci/mmol)) is added and the reaction is incubated at about 30° C. forabout 10 minutes. The reaction mixture is spotted (20 μL) onto a 2 cm×2cm P81 (phosphocellulose, for positively charged peptide substrates) orWhatman No, 1 (for Poly (Glu-4-Tyr) peptide substrate) paper square. Theassay squares are washed 4 times, for 5 minutes each, with 0.75%phosphoric acid and washed once with acetone for 5 minutes. The assaysquares are transferred to a scintillation vial, 5 ml scintillationcocktail are added and ³²P incorporation (cpm) to the peptide substrateis quantified with a Beckman scintillation counter. Percentageinhibition is calculated for each reaction.

Compounds of Formula I, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Forexample, compounds of Formula I preferably show an IC₅₀ in the range of1×10⁻¹⁰ to 1×10⁻⁵ M, preferably less than 50 nM for wild type BCR-Abland G250E, E255V, T315L F317L and M351T BCR-Abl mutants. Compounds ofFormula I preferably, at a concentration of 10 μM, preferably show apercentage inhibition of greater than 50%, preferably greater than about70%, against Ab1 Bcr-ab1, Bmx, c-RAF, CSK, Fes, FGFR3, Flt3, GSK3β, IR,JNK1α1, JNK2α2, Lck, MKK4, MKK6, p70S6K, PDGFRα, Rsk1, SAPK2α, SAPK2β,Syk and TrkB kinases. For example:

-   a).    N-{4-Methyl-3-[8-methyl-2-(6-methyl-pyridin-3-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide    (Example 2) has an IC₅₀ of <0.5 nM, 23 nM, 13 nM, 55 nM <0.5 nM and    <0.5 mM for wild type, G250E, E255V, T315I F317L and M351T Bcr-abl,    respectively; and-   b).    N-{4-Methyl-3-[8-methyl-2-(6-methyl-pyridin-3-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]phenyl}-3-trifluoromethyl-benzamide    (Example 2), at a concentration of 10 μM, inhibits the following    kinases by the percentage shown in brackets (for example, 100% means    complete inhibition, 0% means no inhibition): Bmx (100%), c-RAF    (100%), CSK (98%), Fes (100%), FGFR₃ (98%), Flt3 (64%), GSK3β (53%),    IR (60%), JNK1α1 (98%), JNK2α2 (99%), Lck (98%), MKK4 (92%), MKK6    (97%), p70S6K (98%), PDGFRα (76%), Rsk1 (90%), SAPK2α (95%), SAPK2β    (99%), Syk (76%) and TrkB (96%).

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of formula I:

in which: Y is selected from C, P(O), and S(O); R₁ is selected fromhydrogen, C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,C₃₋₁₀cycloalkyl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; R₂ isselected from hydrogen and C₁₋₆alkyl; or R₁ and R₂ together with thenitrogen atom to which R₁ and R₂ are attached form C₃₋₁₀heterocycloalkylor C₅₋₁₀heteroaryl; wherein any alkyl of R₁ can be optionallysubstituted by one to three radicals independently chosen from halo,C₁₋₆alkoxy and —XNR₇R₈; wherein X is a bond or C₁₋₆alkylene; and R₇ andR₉ are independently chosen from hydrogen and C₁₋₆alkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁, or thecombination of R₁ and R₂, is optionally substituted by one to threeradicals chosen from halo, hydroxy, C₁₋₆alkyl, —XOXNR₇R₈ and —XR₁₀;wherein X is a bond or C₁₋₆alkylene; R₇ and R₈ are independently chosenfrom hydrogen and C₁₋₆alkyl; and R₁₀ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl and C₃₋₁₀heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₀ is optionallysubstituted by 1 to 3 radicals chosen from halo, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy and —XNR₇R₈radicals; wherein X is a bond or C₁₋₆alkylene; and R₇ and R₈ areindependently chosen from hydrogen and C₁₋₆alkyl; R₃ and R₄ areindependently chosen from hydrogen and C₁₋₆alkyl; R₅ is selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₄alkoxy; R₆ is selected from C₆₋₁₀aryl,C₅₋₁₀heteroaryl, C₃₋₁₀cycloalkyl and C₃₋₁₀heterocycloalkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₆ is optionallysubstituted by one to three radicals independently chosen from halo,amino, nitro, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted C₁₋₆alkoxy, —XNR₇R₇, —XNR₇XNR₇R₇, —XNR₇C(O)R₇,—XC(O)OR₇, —XNR₇S(O)₂R₇, —XNR₇S(O)R₇, —XNR₇SR₇ and —XR₁₁; wherein X andR₇ are as defined above and R₁₁ is selected from the group consisting ofC₅₋₁₀heteroaryl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; whereinany heteroaryl or heterocycloalkyl of R₁₁ is optionally substituted witha radical selected from the group consisting of C₁₋₆alkyl,halo-substituted-C₁₋₆alkyl and —C(O)OR₇; and the pharmaceuticallyacceptable salts, hydrates, solvates and isomers thereof.
 2. Thecompound of claim 1 in which: Y is C; R₁ is selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl-C₀₋₄-alkyl, C₅₋₁₀heteroaryl-C₀₋₄alkyl,C₃₋₁₀cycloalkyl-C₀₋₄alkyl and C₃₋₁₀heterocycloalkyl-C₀₋₄-alkyl; R₂ isselected from hydrogen and C₁₋₆alkyl; or R₁ and R₂ together with thenitrogen atom to which R₁ and R₂ are attached formC₃₋₁₀heterocycloalkyl; wherein any alkyl of R₁ can be optionallysubstituted by one to three radicals independently chosen fromC₁₋₆alkoxy and —XNR₇R₉; wherein X is a bond or C₁₋₆alkylene; and R₇ andR₅ are independently chosen from hydrogen and C₁₋₆alkyl; wherein anyaryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁, or thecombination of R₁ and R₂, is optionally substituted by one to threeradicals chosen from hydroxy, C₁₋₆alkyl, —XOXNR₇R₅ and —XR₁₀; wherein Xis a bond or C₁₋₆alkylene; R₇ and R₉ are independently chosen fromhydrogen and C₁₋₆alkyl; and R₁₀ is selected from C₆₋₁₀aryl andC₃₋₁₀heterocycloalkyl; wherein any aryl or heterocycloalkyl of R₁₀ isoptionally substituted by 1 to 3 radicals chosen from halo, C₁₋₆alkyland —XNR₇R₅ radicals; wherein X is a bond or C₁₋₆alkylene; and R₇ and R₉are independently chosen from hydrogen and C₁₋₆alkyl; R₃, R₄ and R₅ areindependently chosen from hydrogen and C₁₋₆alkyl; R₆ is C₆₋₁₀aryloptionally substituted by 1 to 3 radicals independently chosen fromhalo-substituted-C₁₋₆alkyl and —XR₁₁; wherein X is as defined above andR₁₁ n is selected from the group consisting of C₅₋₁₀heteroaryl-C₀₋₄alkyland C₃₋₁₀heterocycloalkyl-C₀₋₄alkyl; wherein any heteroaryl orheterocycloalkyl of R₁₁ is optionally substituted with C₁₋₆alkyl.
 3. Thecompound of claim 2 in which: R₁ is selected from hydrogen, methyl,ethyl, 6-methyl-pyridin-3-yl, 3-(2-oxo-pyrrolidin-1-yl)-propyl,pyridin-3-yl, 3-methyl-isothiazol-5-yl, methoxy-ethyl, isopropyl,methyl-phenyl, morpholino-ethyl, cyclopropyl, diethyl-amino-ethyl,pyrrolidinyl-ethyl, pyridinyl-methyl, 4-hydroxy-cyclohexyl,benzo[1,3]dioxol-5-yl, 4-morpholino-phenyl, 3-dimethylamino-phenyl,4-(2-morpholin-4-yl-ethyl)-phenyl and diethyl-amino-ethoxy; R₂ isselected from hydrogen, methyl and ethyl; or R₁ and R₂ together with thenitrogen atom to which R₁ and R₂ are attached form 4-ethyl-piperazinylor 4-(3-amino-phenyl)-piperazin-1-yl.
 4. The compound of claim 3 inwhich R₃ is methyl, R₄ is methyl and R₅ is hydrogen.
 5. The compound ofclaim 4 in which R$ is phenyl optionally substituted with 1 to 2radicals selected from trifluoromethyl, morpholino, methyl-imidazolyl,methyl-piperazinyl-methyl, ethyl-piperazinyl and methyl-piperazinyl. 6.The compound of claim 5 selected from:N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-morpholin-4-yl-5-trifluoromethyl-benzamide;N-[4-methyl-3-(8-methyl-2-(6-methyl-pyridin-3-ylamino)7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydropteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-[4-methyl-3-[8-methyl-2-[4-(morpholin-4-ylphenylamino]-7-oxo-7,8-dihydropteridin-6-yl]-phenyl]-3-trifluoromethyl-benzamide;N-[3-(2-Dimethylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-(3-{2-[(2-Methoxy-ethyl)-methyl-amino]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-[3-(2-Isopropylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-7-oxo-2-p-tolylamino-7,8-dihydro-pteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-2-(2-morpholin-4-yl-ethylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(4-Ethyl-piperazin-1-yl)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Cyclopropylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(2-Diethylamino-ethylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-7-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-7-oxo-2-[(pyridin-4-ylmethyl)-amino]-7,8-dihydro-pteridin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;N-[3-(2-Diethylamino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(4-Hydroxy-cyclohexylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(Benzo[1,3]dioxol-5-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(3-{2-[4-(3-Amino-phenyl)-piperazin-1-yl]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;N-{3-[2-(3-Dimethylamino-phenylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-7-oxo-7,8-dihydro-pteridin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;N-(3-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl}-4-methyl-phenyl)-3-trifluoromethyl-benzamide;3-(4-Methyl-imidazol-1-yl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-5-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-4-morpholin-4-yl-3-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[2-methylamino-8-(2-morpholin-4-yl-ethyl)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide;N-(4-Methyl-3-{8-methyl-7-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-7,8-dihydro-pteridin-6-yl}-phenyl)-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-7-oxo-2-(pyridin-3-ylamino)-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-2-(3-methyl-isothiazol-5-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(2,5-Dimethyl-2H-pyrazol-3-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;3-(4-Ethyl-piperazin-1-yl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-5-trifluoromethyl-benzamide;N-[4-Methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide;4-(4-Ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(8-methyl-2-methylamino-7-oxo-7,8-dihydro-pteridin-6-yl)-phenyl]-3-trifluoromethyl-benzamide;N-{3-[2-(2,6-Dimethyl-pyridin-3-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-{4-Methyl-3-[8-methyl-2-(2-methyl-pyridin-3-ylamino)-7-oxo-7,8-dihydro-pteridin-6-yl]-phenyl}-3-trifluoromethyl-benzamide;N-{3-[2-(4,6-Dimethyl-pyridin-3-ylamino)-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl]-4-methyl-phenyl}-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-4-morpholin-4-yl-3-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-morpholin-4-yl-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-ethyl-piperazin-1-yl)-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-benzamide;N-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide;andN-[3-(2-Amino-8-methyl-7-oxo-7,8-dihydro-pteridin-6-yl)-4-methyl-phenyl]-4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide.7. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Claim 1 in combination with a pharmaceuticallyacceptable excipient.
 8. A method for treating a disease in an animal inwhich inhibition of kinase activity can prevent, inhibit or amelioratethe pathology and/or symptomology of the disease, which method comprisesadministering to the animal a therapeutically effective amount of acompound of Claim
 1. 9. The method of claim 8 in which the kinase isselected from the group consisting of Abl, Bcr-abl, Bmx, c-RAF, CSK,Fes, FGFR3, Flt3, GSK3β, IR, JNK1β1, JNK2α2, Lck, MKK4, MKK6, p70S6K,PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and TrkB.
 10. The use of a compound ofclaim 1 in the manufacture of a medicament for treating a disease in ananimal in which the kinase activity of Abl, Bcr-abl, Bmx, c-RAF, CSK,Fes, FGFR3, Flt3, GSK3β, IR, JNK1α1, JNK2α2, Lck, MKK4, MKK6, p70S6K,PDGFRα, Rsk1, SAPK2α, SAPK2β, Syk and TrkB contributes to the pathologyand/or symptomology of the disease.